Neutral fats (sometimes referred to as triglycerol or triacylglycerol. Hereinafter, sometimes abbreviated as TG or TAG) are synthesized primarily in the small intestine, the liver and adipose tissues. Dietary-derived fats are degraded in the gastrointestinal tract and then taken up by small-intestinal epithelial cells. After resynthesis into neutral fats in the cells, the neutral fats are packaged into chylomicrons and secreted into the lymphatics. The secreted chylomicrons are degraded by lipoprotein lipase primarily into free fatty acids and chylomicron remnants. The free fatty acids are taken up by peripheral tissues such as skeletal muscles and utilized as energy, or an excess of the free fatty acids is taken up by adipose tissues, resynthesized into neutral fats, and then accumulates. On the other hand, the chylomicron remnants are taken up by chylomicron remnant receptors in the liver and degraded. In the liver, degraded fats are resynthesized into neutral fats, packaged into lipoproteins and secreted. In this way, living bodies sequentially metabolize fats primarily in the liver, the small intestine and adipose tissues to maintain the homeostasis of neutral fats in the blood.
However, the homeostasis is disrupted when dietary-derived fats excessively enter the body because of nutritional excess in recent years. As a result, neutral fat synthesis is excessively increased, which causes obesity. Further, enlarged fat cells characterized by obesity secrete malignant, physiologically active substances including TNFα, cause insulin resistance and gluconeogenesis, and induce type II diabetes.
Although superior antiobesity agents are desired, there is currently no drug satisfactory in terms of drug efficacy and safety. Orlistat, a fat absorption inhibitor, causes gastrointestinal symptoms including steatorrhea, and sibutramine, an anorexiant, has cardiovascular adverse effects. For these reasons, the development of drugs better in terms of both drug efficacy and safety is desired.
These days, the mechanisms of neutral fat synthesis and fat absorption in small-intestinal epithelial cells are being elucidated. 2-Monoacylglycerol and free fatty acids which are formed by degradation in the gastrointestinal tract by pancreatic lipase are each absorbed into small-intestinal epithelial cells. Next, the acyl group of the free fatty acid is transferred to 2-monoacylglycerol by monoacylglycerol acyltransferase. Further, diacylglycerol produced is converted into neutral fats by diacylglycerol acyltransferase (hereinafter, sometimes abbreviated as DGAT).
In 2003, the clonings of mouse MGAT2 and human MGAT2 were successively reported (see Non-Patent Documents 1 and 2). The enzyme was found to be expressed in small-intestinal epithelial cells and to exhibit MGAT activity that transfers an acyl group to 2-monoacylglycerol. Based on this finding, it was speculated that the enzyme might be responsible for MGAT activity in small-intestinal epithelial cells.
In 2004, high-fat feeding was reported to increase MGAT2 expression in the small intestine (see Non-Patent Document 3). In proportion thereto, the increase of MGAT activity in the small intestine was also observed.
In 2010, MGAT2 knockout mice were reported (see Non-Patent Document 4). The mice have been found to be free of abnormal general findings. Further, based on the finding that fat absorption was delayed in the mice, MGAT2 was confirmed as MGAT that plays a major role in fat absorption in small-intestinal epithelial cells. The knockout mice, when fed on a normal diet, had no difference in body weight from normal mice. However, in the MGAT2 knockout mice fed on a high-fat diet, body weight increase, which was observed in normal mice, was strongly inhibited. Moreover, increases of blood cholesterol and fatty liver, which are to be caused by high-fat feeding, were inhibited. Induction of impaired glucose tolerance was also inhibited.
Based on these findings, it is speculated that a substance inhibiting MGAT2 (hereinafter referred to as MGAT2-inhibiting substance or MGAT2 inhibitor) can inhibit neutral fat synthesis in small-intestinal epithelial cells and can inhibit or delay fat absorption. Further, in the modern society, which is characterized by nutritional excess and insufficient exercise, an MGAT2-inhibiting substance is expected to serve as an ideal antiobesity agent or antihyperlipidemic agent that has a strong body weight-lowering effect. An MGAT2-inhibiting substance is also expected to inhibit the progress of type II diabetes, which is induced by obesity. In addition, long-term administration of an MGAT2-inhibiting substance is expected to correct or prevent arteriosclerosis, fatty liver and hypertension.
As MGAT2 inhibitors, compounds having a bicyclic pyrimidine skeleton are reported (see Patent Documents 1 and 2). Further, as Na channel blockers unrelated to MGAT2 inhibitors, compounds having a nitrogen-containing condensed heterocyclic structure are reported; however, the compounds of the present invention as shown below are not disclosed (see Patent Document 3).